Our objective in this work is to study factors that contribute to human susceptibility to cutaneous malignancy. We want to know why some persons with certain heritable disorders and some who have been exposed to environmental mutagens develop more skin cancers than normal. We are concerned with the long-term and short-term biological consequences of photomediated, covalent psoralen-DNA photoadducts such as are produced by photochemotherapy (PUVA) with 8-methoxypsoralen (8-MOP) and UV-light (365 nm). After in vitro binding by UV-A of 4,5'8 trimethylpsoralen (TMP) and 8-MOP we are comparing cutaneous cells and lymphocytes from persons in normal and disease states with respect to cell growth and survival; and repair of psoralen DNA cross-links. We are using cells from persons with dyskeratosis congenita, xeroderma pigmentosum and their relatives. We are also measuring concentrations of psoralens in blood of our PUVA patients and correlating these values with the patients' phototoxic and therapeutic responses. We are comparing the cross-linking capabilities of several different psoralens.